Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.6.5.3 (complex I)
8,901 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mitochondrial respiration, succinate dehydrogenase coenzyme Q reductase, and myosin B were investigated in ischemic myocardium from experimental myocardial infarction in dogs. Respiratory control ratio of mitochondria was impaired by ischemia at 60 min after coronary ligation, and oxygen consumption was inhibited 120 min later. Enzyme activity of succinate dehydrogenase coenzyme Q reductase was decreased at 6 hr after coronary ligation. Calcium ion sensitivity of myosin B declined 12 hr after coronary ligation. However, adenosine triphosphatase activity of myosin A from infarcted myocardium was not different from that of the intact one. These results suggest that interaction in the sequence of enzyme complexes was first impaired in ischemic myocardium and that deterioration of enzyme activity was then manifested.
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PMID:Relationship between energy liberation and utilization in ischemic cardiac muscle. 103 51

The effect of alpha-tocopherol pretreatment (6 mg/100 g body wt/day, orally for a period of 90 days) on mitochondrial electron transport in myocardial infarction induced by isoproterenol (20 mg/100 g body wt, subcutaneously for two days) was studied in rats. A significant decrease was observed in the activities of isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, NADH dehydrogenase and cytochrome oxidase in heart mitochondria of isoproterenol administered rats. The cytochrome content and the oxidation of succinate in state 3 and state 4 decreased significantly in the cardiac mitochondria treatment. In alpha-tocopherol pretreated rats, the activities of TCA cycle enzymes, concentration of cytochromes and the oxidation of succinate in state 3 and state 4 were retained at near normal values, following isoproterenol administration.
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PMID:Effect of alpha-tocopherol on mitochondrial electron transport in experimental myocardial infarction in rats. 975 71

Mitochondria are one of the enzymatic sources of reactive oxygen species (ROS) and could also be a major target for ROS-mediated damage. We hypothesized that ROS may induce mitochondrial DNA (mtDNA) damage, which leads to defects of mtDNA-encoded gene expression and respiratory chain complex enzymes and thus may contribute to the progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). In a murine model of MI and remodeling created by the left anterior descending coronary artery ligation for 4 weeks, the LV was dilated and contractility was diminished. Hydroxyl radicals, which originated from the superoxide anion, and lipid peroxide formation in the mitochondria were both increased in the noninfarcted LV from MI mice. The mtDNA copy number relative to the nuclear gene (18S rRNA) preferentially decreased by 44% in MI by a Southern blot analysis, associated with a parallel decrease (30% to 50% of sham) in the mtDNA-encoded gene transcripts, including the subunits of complex I (ND1, 2, 3, 4, 4L, and 5), complex III (cytochrome b), complex IV (cytochrome c oxidase), and rRNA (12S and 16S). Consistent with these molecular changes, the enzymatic activity of complexes I, III, and IV decreased in MI, whereas, in contrast, complex II and citrate synthase, encoded only by nuclear DNA, both remained at normal levels. An intimate link among ROS, mtDNA damage, and defects in the electron transport function, which may lead to an additional generation of ROS, might play an important role in the development and progression of LV remodeling and failure.
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PMID:Mitochondrial DNA damage and dysfunction associated with oxidative stress in failing hearts after myocardial infarction. 1124 77

Vascular diseases like thrombosis, myocardial infarction, cerebral ischemia or chronic venous insufficiency affect a high proportion of the population. They are all associated with more or less pronounced ischemic conditions. We have previously shown that some venotropic drugs display an anti-ischemic activity, i.e. they prevent the hypoxia-induced decrease in ATP content in cultured cells. The effect is due to the fact that these molecules maintain mitochondrial respiratory activity during hypoxia. Among them is bilobalide. Starting from the 3D structure of bilobalide, we designed new molecules presenting the same chemical features. They were synthesized and tested for their biological activity. As the parent compound, two of them, malonic acid dicyclopent-2-enyl ester (MRC2P119) and 2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester (MRC2P57), were able to markedly increase the respiratory control ratio of isolated mitochondria. They are able to prevent the inhibition of complex I by amytal and of complex III by myxothiazol, but not the uncoupling of the respiration by carbonylcyanide m-chlorophenyl hydrazone (m-CCP). Moreover, MRC2P119 and MRCP2P57 inhibit, in a dose-dependent way, the hypoxia-induced decrease in ATP content in endothelial cells as well as the subsequent activation of these cells as evidenced by an inhibition of the increase in neutrophil adherence to the endothelial cells induced by hypoxia. Finally, MRC2P119 prevent the hypoxia- and the hypoxia-reoxygenation-induced decrease in viability of SH-SY5Y neuroblastoma cells. In conclusion, we identified two new molecules, which display anti-ischemic properties when tested in vitro on endothelial and neuronal cell types. This anti-ischemic activity is probably due to a protection of complexes I and III of the mitochondrial respiratory chain.
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PMID:Mitochondrial respiratory chain as a new target for anti-ischemic molecules. 1200 18

Although it has been shown that endothelial nitric oxide synthase (eNOS)-derived nitric oxide downregulates mitochondrial oxygen consumption during early reperfusion, its effects on inducible NOS (iNOS) induction and myocardial injury during late reperfusion are unknown. Wild-type (WT) and eNOS(-/-) mice were subjected to 30 min of coronary ligation followed by reperfusion. Expression of iNOS mRNA and protein levels and peroxynitrite production were lower in postischemic myocardium of eNOS(-/-) mice than levels in WT mice 48 h postreperfusion. Significantly improved hemodynamics (+/-dP/dt, left ventricular systolic pressure, mean arterial pressure), increased rate pressure product, and reduced myocardial infarct size (18 +/- 2.5% vs. 31 +/- 4.6%) were found 48 h after reperfusion in eNOS(-/-) mice compared with WT mice. Myocardial infarct size was also significantly decreased in WT mice treated with the specific iNOS inhibitor 1400W (20.5 +/- 3.4%) compared with WT mice treated with PBS (33.9 +/- 5.3%). A marked reperfusion-induced hyperoxygenation state was observed by electron paramagnetic resonance oximetry in postischemic myocardium, but Po(2) values were significantly lower from 1 to 72 h in eNOS(-/-) than in WT mice. Cytochrome c-oxidase activity and NADH dehydrogenase activity were significantly decreased in postischemic myocardium in WT and eNOS(-/-) mice compared with baseline control, respectively, and NADH dehydrogenase activity was significantly higher in eNOS(-/-) than in WT mice. Thus deficiency of eNOS exerted a sustained beneficial effect on postischemic myocardium 48 h after reperfusion with preserved mitochondrial function, which appears to be due to decreased iNOS induction and decreased iNOS-derived peroxynitrite in postischemic myocardium.
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PMID:Endothelial nitric oxide synthase (NOS3) knockout decreases NOS2 induction, limiting hyperoxygenation and conferring protection in the postischemic heart. 1711 45

Dietary flavonoids intake has been reported inversely related to the incidence of cardiovascular diseases (CVD). The present study is undertaken to evaluate the preventive role of naringin on mitochondrial enzymes in isoproterenol (ISO)-induced myocardial infarction in male albino Wistar rats. Rats subcutaneously injected with ISO (85 mg/kg) at an interval of 24 h for 2 days, resulting in significant (p < 0.05) increase in the levels of mitochondrial lipid peroxides. ISO-induction also showed significant (p < 0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, and alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome c oxidase). Oral pretreatment with naringin (10, 20, and 40 mg/kg) to ISO-induced rats daily for a period of 56 days significantly (p < 0.05) minimized the alterations in all the biochemical parameters and restored the normal mitochondrial function. Transmission electron microscopic (TEM) observations also correlated with these biochemical findings. Thus, our findings demonstrate that naringin prevents the mitochondrial dysfunction during ISO-induced myocardial infarction in rats.
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PMID:Preventive effect of naringin on cardiac mitochondrial enzymes during isoproterenol-induced myocardial infarction in rats: a transmission electron microscopic study. 1799 77

The present study investigates the effect of aspartate and glutamate on mitochondrial function during myocardial infarction (MI) in wistar rats. Male albino wistar rats were pretreated with aspartate [100 mg(kgbody weight)(-1) day(-1)] or glutamate [100 mg(kg body weight)(-1) day(-1)] intraperitoneally for a period of 7 days. Following amino acid treatment, MI was induced in rats by subcutaneous injection of isoproterenol [200 mg(kg body weight)(-1) day(-1)] for 2 days at an interval of 24 h. Isoproterenol (ISO) induction resulting in significant (P<0.05) increase in the levels of cardiac mitochondrial lipid peroxidation with a decrease in reduced glutathione level. The activities of glutathione peroxidase and glutathione reductase were significantly (P<0.05) decreased by ISO. ISO-induction also caused significant (P<0.05) decrease in the activities of mitochondrial tricarboxylic acid cycle enzymes (malate dehydrogenase, isocitrate dehydrogenase, succinate dehydrogenase, alpha-ketoglutarate dehydrogenase) and respiratory chain enzymes (NADH dehydrogenase and cytochrome-c-oxidase). ISO significantly (P<0.05) reduced the cytochrome contents, ATP production, ADP/O ratio and oxidation of succinate in state 3/state 4 whereas significantly (P<0.05) increased NADH oxidation. Pretreatment with aspartate or glutamate significantly (P<0.05) reduced the alterations induced by ISO and maintained normal mitochondrial function. The present findings reveal the protective effect of aspartate and glutamate on cardiac mitochondrial function in myocardial infarction-induced rats.
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PMID:Protective effect of aspartate and glutamate on cardiac mitochondrial function during myocardial infarction in experimental rats. 1878 22

Deaths from microcystin toxication have widely been attributed to hypovolemic shock due to hepatic interstitial hemorrhage, while some recent studies suggest that cardiogenic complication is also involved. So far, information on cardiotoxic effects of MC has been rare and the underlying mechanism is still puzzling. The present study examined toxic effects of microcystins on heart muscle of rats intravenously injected with extracted MC at two doses, 0.16LD(50) (14 microg MC-LReq kg(-1) body weight) and 1LD(50) (87 microg MC-LReq kg(-1) body weight). In the dead rats, both TTC staining and maximum elevations of troponin I levels confirmed myocardial infarction after MC exposure, besides a serious interstitial hemorrhage in liver. In the 1LD(50) dose group, the coincident falls in heart rate and blood pressure were related to mitochondria dysfunction in heart, while increases in creatine kinase and troponin I levels indicated cardiac cell injury. The corresponding pathological alterations were mainly characterized as loss of adherence between cardiac myocytes and swollen or ruptured mitochondria at the ultrastructural level. MC administration at a dose of 1LD(50) not only enhanced activities and up-regulated mRNA transcription levels of antioxidant enzymes, but also increased GSH content. At both doses, level of lipid peroxides increased obviously, suggesting serious oxidative stress in mitochondria. Simultaneously, complex I and III were significantly inhibited, indicating blocks in electron flow along the mitochondrial respiratory chain in heart. In conclusion, the findings of this study implicate a role for MC-induced cardiotoxicity as a potential factor that should be considered when evaluating the mechanisms of death associated with microcystin intoxication in Brazil.
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PMID:The profound effects of microcystin on cardiac antioxidant enzymes, mitochondrial function and cardiac toxicity in rat. 1913 22

The reversible S-nitrosation and inhibition of mitochondrial complex I is a potential mechanism of cardioprotection, recruited by ischemic preconditioning (IPC), S-nitrosothiols, and nitrite. Previously, to exploit this mechanism, the mitochondrial S-nitrosating agent S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) was developed, and protected perfused hearts and isolated cardiomyocytes against ischemia-reperfusion (IR) injury. In the present study, the murine left anterior descending coronary artery (LAD) occlusion model of IR injury was employed, to determine the protective efficacy of SNO-MPG in vivo. Intraperitoneal administration of 1 mg/kg SNO-MPG, 30 min prior to occlusion, significantly reduced myocardial infarction and improved EKG parameters, following 30 min occlusion plus 2 or 24 h reperfusion. SNO-MPG protected to the same degree as IPC, and notably was also protective when administered at reperfusion. Cardioprotection was accompanied by increased mitochondrial protein S-nitrosothiol content, and inhibition of complex I, both of which were reversed after 2 h reperfusion. Finally, hearts from mice harboring a heterozygous mutation in the complex I NDUSF4 subunit were refractory to protection by either SNO-MPG or IPC, suggesting that a fully functional complex I, capable of reversible inhibition is critical for cardioprotection. Overall, these results are consistent with a role for mitochondrial S-nitrosation and complex I inhibition in the cardioprotective mechanism of IPC and SNO-MPG in vivo.
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PMID:In vivo cardioprotection by S-nitroso-2-mercaptopropionyl glycine. 1933 6

Complex I (NQR) is a critical site of superoxide (O2-*) production and the major host of redox protein thiols in mitochondria. In response to oxidative stress, NQR-derived protein thiols at the 51- and 75-kDa subunits are known to be reversibly S-glutathionylated. Although several glutathionylated domains from NQR 51 and 75 kDa have been identified, their roles in the regulatory functions remain to be explored. To gain further insights into protein S-glutathionylation of complex I, we used two peptides of S-glutathionylated domain ((200)GAGAYICGEETALIESIEGK(219) of 51-kDa protein and (361)VDSDTLCTEEVFPTAGAGTDLR(382) of 75-kDa protein) as chimeric epitopes incorporating a "promiscuous" T-cell epitope to generate two polyclonal antibodies, AbGSCA206 and AbGSCB367. Binding of AbGSCA206 and AbGSCB367 inhibited NQR-mediated O2-* generation by 37 and 57%, as measured by EPR spin-trapping. To further provide an appropriate control, two peptides of non-glutathionylated domain ((21)SGDTTAPKKTSFGSLKDFDR(40) of 51-kDa peptide and (100)WNILTNSEKTKKAREGVMEFL(120) of 75-kDa peptide) were synthesized as chimeric epitopes to generate two polyclonal antibodies, Ab51 and Ab75. Binding of A51 did not affect NQR-mediated generation to a significant level. However, binding of Ab75 inhibited NQR-mediated O2-*generation by 35%. None of AbGSCA206, AbGSCB367, Ab51, or Ab75 showed an inhibitory effect on the electron transfer activity of NQR, suggesting that antibody binding to the glutathione-binding domain decreased electron leakage from the hydrophilic domain of NQR. When heart tissue homogenates were immunoprecipitated with Ab51 or Ab75 and probed with an antibody against glutathione, protein S-glutathionylation was enhanced in post-ischemic myocardium at the NQR 51-kDa subunit, but not at the 75-kDa subunit, indicating that the 51-kDa subunit of flavin subcomplex is more sensitive to oxidative stress resulting from myocardial infarction.
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PMID:Peptide-based antibodies against glutathione-binding domains suppress superoxide production mediated by mitochondrial complex I. 1994 Jan 58


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